CD4 is surface molecule that serves as the receptor for human immunodeficiency virus (HIV), the causative agent of AIDS. We have focused on two areas related to CD4 and HIV: 1) Mechanisms of membrane fusion mediated by the interaction of CD4 with the HIV-1 envelope glycoprotein (env). One goal of this work is to identify regions of each molecule involved in fusion, and to characterize fusion-related changes in env structure induced upon interaction with CD4. Site- directed mutagenesis studies indicated that CD4 molecules containing a wide variety of mutations in the CDR3 region efficiently support membrane fusion. Mutation of this region also had no effect on the ability of soluble CD4 to induce a specific structural change in env (gp120 stripping). These results challenge the prevailing notion that the CDR3 region plays a critical role in the fusion process. Furthermore, a region of gp120 (V3) believed to participate in fusion appears not to be involved in CD4-induced gp120 stripping, based on studies with fusion-defective V3 mutants. A second goal is to identify additional molecular components involved in fusion. We have demonstrated that human cells can provide to CD4-expressing non-human cells a component(s) which is essential for env-mediated membrane fusion. The critical involvement of calcium ions in the fusion process has also been demonstrated. We are actively developing new systems and assays to study the fusion process, to be applied towards mechanistic studies of membrane fusion and the selective tropism of different HIV isolates for different CD4+ cell types.